Heavy habitual consumption of alcohol leads to progressive injury and fibrosis in several tissues, including the liver. However, many heavy drinkers do not develop advanced liver fibrosis (i.e., cirrhosis) despite years of alcohol abuse. More modest consumption of alcohol (<2drinks/day) has actually been associated with certain health benefits, such as protection from cardiovascular disease. The effects of modest alcohol consumption on the liver have been difficult to predict, however, because evidence suggests that this inhibits fibrosis progression in some types of liver injury (e.g., nonalcoholic fatty liver disease - NAFLD) but accelerates the evolution of cirrhosis in others (e.g., chronic hepatitis C - HCV). Research is needed to clarify the mechanisms that account for the diverse hepatic responses to alcohol. This project is grounded in the HYPOTHESIS that alcohol consumption provokes epigenetic events that modify liver repair responses that are specified by the underlying genetic profile. Our Specific Aims are: 1) to determine if a) there are liver gene expression and/or epigenetic signatures for advanced liver fibrosis and b) alcohol consumption influences this fibrogenic profile; 2) to identify gene polymorphisms that associate with susceptibility to alcohol-related alterations in the fibrogenic profile; 3) to determine the effects of SAMe deficiency and SAMe supplementation on epigenetic modifications and the liver gene expression profile for advanced liver fibrosis in individuals with alcohol-induced cirrhosis. We will take advantage of large well-annotated bio-repositories that house frozen liver samples, serum/plasma, DNA, and clinical information from patients with NAFLD, chronic HCV, and alcoholic liver disease (ALD). The largest and most comprehensive tissue collection was obtained from >1000 patients with NAFLD and includes sizeable sub-populations who are either non-drinkers or social drinkers. Therefore, initial work in Aims 1 &2 will focus on characterizing the liver gene expression, epigenetic signature and haplotype profiles of these groups. Parallel liver gene expression and epigenetic analyses will be conducted in non- drinking and modest drinkers with chronic HCV, our next largest cohort. Because liver biopsies are not generally indicated in patients with ALD, analysis will be restricted to cirrhotic ALD samples that were acquired at the time of liver transplantation or during an already approved and funded clinical protocol that is investigating the effects of SAMe on liver fibrosis. In aggregate, these studies will provide novel information about how alcohol induces epigenetic events that modulate hepatic expression of genes that regulate liver fibrosis, and identify gene polymorphisms that influence these responses. Such knowledge will help to guide recommendations about the risk/benefits of alcohol use, particularly in individuals with underlying liver disease. This has important public health implications given the fact that social use of alcohol is virtually ubiquitous. PUBLIC HEALTH RELEVANCE: These studies will provide novel information about how alcohol induces epigenetic events that modulate hepatic expression of genes that regulate liver fibrosis, and identify gene polymorphisms that influence these responses. Such knowledge will help to guide recommendations about the risk/benefits of alcohol use, particularly in individuals with underlying liver disease. This has important public health implications given the fact that social use of alcohol is virtually ubiquitous.